Phase III HEAT Study Adding Lyso-Thermosensitive Liposomal Doxorubicin to Radiofrequency Ablation in Patients With Unresectable Hepatocellular Carcinoma Lesions

Purpose: Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of doxorubicin contained within a heat-sensitive liposome. When heated to >=40ºC, LTLD locally releases a high concentration of doxorubicin. We aimed to determine whether adding LTLD improves the efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) lesions with a maximum diameter (dmax) of 3 to 7 cm. Patients and Methods: The HEAT Study was a randomized, double-blind, dummy-controlled trial of RFA +/- LTLD. The 701 enrolled patients had to have <=4 unresectable HCC lesions, at least 1 of which had a dmax of 3 to 7 cm. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). Post hoc subset analyses investigated whether RFA duration was associated with efficacy. Results: The primary endpoint was not met; in intention-to-treat analysis, the PFS hazard ratio (HR) of RFA + LTLD vs RFA alone was 0.96 (95% confidence interval [CI]: 0.79-1.18; P=0.71) and the OS HR ratio was 0.95 (95% CI: 0.76-1.20; P=0.67). Among 285 patients with a solitary HCC lesion who received >=45 minutes RFA dwell time, the OS HR was 0.63 (95% CI: 0.41-0.96; P<0.05) in favor of combination therapy. RFA + LTLD had reversible myelosuppression similar to free doxorubicin. Conclusion: Adding LTLD to RFA was safe but did not increase PFS or OS in the overall study population. However, consistent with LTLD's heat-based mechanism of action, subgroup analysis suggested that RFA + LTLD efficacy is improved when RFA dwell time for a solitary lesion >=45 minutes.

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